In vivo therapy with a CD4 (L3T4) monoclonal antibody is able to provide a tolerogenic milieu for a limited number of protein antigens. In this study we have analyzed the mechanisms of such tolerance to human gamma globulin, and show that tolerance is induced in adult T helper cells without a need for cellular depletion, and that it is probably not maintained by suppressor mechanisms nor by regulatory cellular circuits involving CD8+ (Ly-2+) cells. Tolerance induction is not a property peculiar to the CD4 molecule, as similar effects can be elicited with a monoclonal antibody directed to the CD11a (LFA-1) molecule. We suggest that tolerance is maintained by the functional deletion of mature T helper cells and that adhesion molecules, such as CD4, CD8 and CD11a, may play a critical role in T cell discernment of self from nonself.